Chiral 2,3-dihydropyrroles synthesis

Bach T, Brummerhop H (1998) Unprecedented facial diastereoselectivity in the Paterno-Buchi reaction of a chiral dihydropyrrol—A short total synthesis of (+)-preussin. Angew Chem 110 3577-3579, Angew Chem Int Ed 37 3400-3402... 

Very recently, Sun et al. developed a cascade reaction with a binary catalytic system combining a secondary amine and a palladium catalyst for the synthesis of dihydropyrrole enantioselectively [54]. The reaction began with a Jprgensen-Hayashi catalyst promoted N-Ts propargyl amine-involved aza-Michael addition to cinnamaldehydes and ended with subsequent PdCl and Jprgensen-Hayashi catalyst co-promoted car-bocyclization (Scheme 9.59). The chemistry presented here also involved a DYKAT process and provided an alternative to chiral dihyropyrrole synthesis. 

RCM reactions are most frequently employed in the synthesis of 2,5-dihydrofurans as well as dihydropyrrole derivatives . Likewise, RCM provides the most general approach to 3,6-dihydropyrans . In a specific example, dihydropyran 127 bearing a chiral oxacyclic diene can be constructed via enyne metathesis of the chiral ether 126 (Scheme 68) <2002T5627>. The analogous tetrahydropyridine derivatives are prepared by a similar RCM procedure . 

Further progress towards the stereoselective synthesis of chhydrooxazines has also been reported by Reissig and coworkers who exploited the formal [3 + 3] reaction of lithiated methoxyallene with nitrones derived from (R)-glyceraldehyde [97,98]. Subsequent transformations enabled the synthesis of enantiomerically pure pyrrolidine and 2,5-dihydropyrrole derivatives incorporating one asymmetric unit of the chiral template. 

Bach, T., Brummerhop, H., Harms, K. The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buchi reactions of chiral 2-substituted 2,3-dihydropyrroles. Chem.— Eur. J. 2000, 6, 3838-3848. 

Optically pure 2,3-dihydropyrroles are important unsaturated heterocyclic compounds because of their application as chiral building blocks in the organic synthesis and the total synthesis of natural products. However, the asymmetric organocatalytic synthesis of chiral 2,3-dihydropyrroles is scarce. Highly diastereo- and enantiose-lective syntheses of 2,3-dihydropyrroles 14 by the base catalyzed asymmetric... 

Chiral intermediates for the synthesis of (-)-anisomycin (1) and (+)-anisomycin (anti-1) (153), (R)-2-(p-methoxyphenyl)methyl-2,5-dihydro-pyrrole (142) and its (S)-isomer (+)-187, have been efficiently synthesized from D-tyrosine and L-tyrosine, respectively (Scheme 20) [28]. D-tyrosine was converted to 0-methyl D-tyrosine methyl ester (182) [72-75] which was treated with di-tert-butyl dicarbonate to protect the amino group. Subsequent reduction of the ester group with sodium borohydride in the presence of lithium chloride furnished the alcohol 183. Swern oxidation of 183 followed by chain extension with the anion derived from bis(2,2,2-trifluoroethyl)(ethoxycarbonylmethyl)-phosphonate afforded (Z)-Q ,/0-unsaturated ester (184), which was used immediately without purification to avoid or minimize any possible racemization of the chiral center. Reduction of the ester group of 184 with diisobutylaluminium hydride afforded the alcohol 185 which after mesylation followed by intramolecular cyclization gave the desired 2,5-dihydropyrrole derivative 186. Removal of the tert-butyloxycarbonyl group was achieved by treatment with trifuoroacetic acid to give (-)-142 in 62% overall yield from 182. The (S)-2,5-dihydropyrrole (-l-)-187 was also prepared in the same manner starting from L-tyrosine. Since (-l-)-187 had been transformed into (-l-)-anisomycin (anti-1) (153), (-)-142 could also be transformed to the (-)-anisomycin (1) [26,66]. 

A new class of chiral bifunctional thiourea catalysts derived from trans-2-amino-l-(diphenylphosphino)cyclohexane was developed by Jacobsen and Fang in order to be applied to a highly enantioselective synthesis of a wide range of 2-aryl-2,5-dihydropyrrole derivatives. This strategy was based on a [3-1-2] cycloaddition between an A-phosphinoyl imine and an allene in the presence of TEA and water as additives. High yields combined with excellent enantioselectivities of up to 98% ee were observed in all cases of substrates, as shown in Scheme 6.19. 

The phosporic acid (261) catalysed three component reaction involving asymmetric 1,3-dipolar cycloaddition of electron-deficient azomethine ylides (327), aromatic aldehydes (328) and 2-aminomalonates (329) to provide to novel 2,5-dihydropyrrole derivatives (330) with potential bioactivities with enantioselectivities of up to >99% ee (Scheme 86). The Bronsted acids (253) catalysed intermolecular enantioselective alkylation of indoles (332) with cx,p-unsaturated y-lactams (331) thus providing a highly enantioselective method for the synthesis of chiral pyrroli-dinones (333) containing indole moieties, with enantioselectivity (up to 95% ee), has been described by Huang et al. (Scheme 87). " ... 

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